DESCRIPTION: The broad long-term goal of this project is to increase our knowledge of neural processes that contribute to the development and maintenance of alcoholism. A prominent feature of alcoholism is the progression from intermittent alcohol intake to chronic uncontrolled alcohol abuse and dependence. This progressive dependence on alcohol suggests that neuroadaptive responses to repeated alcohol exposure in individuals that are susceptible to alcoholism differ from those of non-alcoholics. The proposed 2 year exploratory (R21) project focuses on a systematic examination of an adaptive response frequently observed in both humans and animals following chronic drug exposure, namely sensitization. Recent theories suggest that sensitization may play an important role in drug abuse. Specifically, the project will investigate the role of both neurochemical and behavioral mechanisms in sensitization to ethanol using the locomotor stimulant effects of ethanol in mice as a model. Parallel studies will be conducted in several mouse genotypes (DBA/2J, FAST, COLD) to increase the generality of experimental results. Initial experiments will explore doses of ethanol that produce robust sensitization in each mouse genotype. Neural mechanisms that contribute to sensitization will then be assessed in a series of experiments. The role of dopamine (DA Dl and D2) and gamma-aminobutyric acid (GABA-A and GABA-B) receptors in sensitization to ethanol will be assessed in experiments using selective GABA agonists and dopamine antagonists to block development of sensitization. The contribution of associative -learning processes and conditioned responses to sensitization will also be assessed in animals receiving equal exposure to ethanol but differing in pairing of ethanol administration with the activity test chambers. Finally, examination of cross-sensitization between ethanol and more thoroughly characterized psychoactive drugs such as amphetamine, cocaine, and morphine will reveal commonalities in neural mechanisms mediating sensitization, and point toward the involvement of specific neural pathways. These studies will provide valuable new information concerning acquisition of sensitization, and the contribution of learning processes and different neurotransmitter systems. Moreover, the data collected will provide a basis for more extensive examination of the mechanisms mediating sensitization to ethanol in future studies.